Fused triazolo-pyrimidine compounds having useful pharmaceutical application

Abstract

A compound and/or a pharmaceutically acceptable salt thereof has the following formula A: These compounds can be PIKfyve kinase inhibitors.

What is claimed is: 
     
       1. A method of treating multiple myeloma, comprising:
 administering a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof: 
 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is alkyl, heterocyclyl, aryl, or heteroaryl, provided R 1  is not cyclohexyl, 
         R 2  is —N═CH-alkyl, —N═CH-aryl or —N═CH-heteroaryl, 
         R 3  and R 4  together with the nitrogen to which they are attached form a mono or bi-cyclic heterocyclyl each of the mono or bi-cyclic heterocyclyl is optionally substituted with one, two, three, or four groups selected from C 1 -C 6  alkyl. 
       
     
     
       2. The method of  claim 1 , wherein the compound has a structure as defined by Formula II 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is alkyl, heterocyclyl, aryl, or heteroaryl, provided R 1  is not cyclohexyl, 
         R 2  is N═CH-alkyl, N═CH aryl or N═CH-heteroaryl, and 
         R 5 , R 6 , R 7 , and R 8  are independently H or methyl. 
       
     
     
       3. The method of  claim 2 , wherein the alkyl, aryl or heteroaryl of R 2  is substituted with one or two groups selected from —F, —Cl, —CN, —OH, —C(O)NH 2 , —CF 3 , —NH 2 , —NHSO 2 —C 1 -C 6  alkyl, —OCF 3 , —O—C 1 -C 6  alkyl, C 1 -C 6  alkyl, phenyl, and mono-cyclic heteroaryl. 
     
     
       4. The method of  claim 3 , wherein R 2  is 
       
         
           
           
               
               
           
         
       
       wherein   indicates the point of attachment to the remaining moiety of the molecule. 
     
     
       5. The method of  claim 2 , wherein R 2  is —N═CH-phenyl or —N═CH-naphthalenyl, wherein the phenyl or naphthalenyl is substituted with one or two groups selected from —F, —Cl, —CN, —OH, —C(O)NH 2 , —CF 3 , —NH 2 , —NHSO 2 —C 1 -C 6  alkyl, —OCF 3 , —O—C 1 -C 6  alkyl, C 1 -C 6  alkyl, phenyl, and mono-cyclic heteroaryl. 
     
     
       6. The method of  claim 2 , wherein R 2  is N═CH-heteroaryl in which heteroaryl is pyridinyl or indolyl, optionally substituted with one or two groups selected from —F, —Cl, —CN, —OH, —C(O)NH 2 , —CF 3 , —NH 2 , —NHSO 2 —C 1 -C 6  alkyl, —OCF 3 , —O—C 1 -C 6  alkyl, C 1 -C 6  alkyl, phenyl, and mono-cyclic heteroaryl. 
     
     
       7. The method of  claim 2 , wherein R 2  is N═CH-alkyl in which alkyl a lower alkyl, optionally substituted with one or two groups selected from —F, —Cl, —CN, —OH, —C(O)NH 2 , —CF 3 , —NH 2 , —NHSO 2 —C 1 -C 6  alkyl, —OCF 3 , —O—C 1 -C 6  alkyl, C 1 -C 6  alkyl, phenyl, and mono-cyclic heteroaryl. 
     
     
       8. The method of  claim 2 , wherein alkyl, heterocyclyl, aryl, or heteroaryl of R 1  is substituted with one or two groups selected from —F, —Cl, —CN, —OH, —C(O)NH 2 , —CF 3 , —NH 2 , —NHSO 2 —C 1 -C 6  alkyl, —OCF 3 , —O—C 1 -C 6  alkyl, C 1 -C 6  alkyl, phenyl, and mono-cyclic heteroaryl. 
     
     
       9. The method of  claim 8 , wherein R 1  is 
       
         
           
           
               
               
           
         
       
       wherein   indicates the point of attachment to the remaining moiety of the molecule. 
     
     
       10. The method of  claim 1 , wherein the mono-cyclic heterocyclyl is aziridine, azetidine, pyrolidine, piperidine, morpholine, piperazine, thiomorpholine, thiomorpholine-S-oxide, thiomorpholine-S,S-dioxide, azepane, 1,4-oxazepane, or 1,4-thiazepane. 
     
     
       11. The method of  claim 1 , wherein R 3  and R 4  together with the nitrogen to which they are attached form one of the following rings: 
       
         
           
           
               
               
           
         
       
       wherein   indicates the point of attachment to the remaining moiety of the molecule. 
     
     
       12. The method of  claim 1 , wherein the compound is selected from the following compounds: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
       13. The method of  claim 1 , wherein the compound is 
       
         
           
           
               
               
           
         
       
     
     
       14. The method of  13 , wherein said administering is orally administering. 
     
     
       15. The method of  claim 14 , wherein said orally administering comprises orally administering a pharmaceutical composition selected from the group consisting of a sterile solution, a suspension, an emulsion, a tablet, a pill, a pellet, a capsule, a powder, a syrup, and an elixir.